Tricyclic fused heterocycle compounds, process for preparing...

Details Tricyclic fused heterocycle compounds, process for preparing... Tricyclic fused heterocycle compounds, process for preparing...

2002-11-12

2004-03-02

Lambkin, Deborah C. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acids and salts thereof

C562S426000

Reexamination Certificate

active

06700013

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel tricyclic condensed heterocyclic compounds, their preparation method and uses. The tricyclic condensed heterocyclic compounds of the present invention have a wide range of pharmacological actions such as the relaxing action of tracheal smooth muscles, the inhibition of airway hypersensitivity and the inhibition of infiltration of inflammatory cells into the airway and are useful as drugs such as antiasthmatic drugs.
BACKGROUND ART
Heretofore, various cyclic compounds have been proposed as the compounds useful for asthma and the like. For example, xanthine derivatives such as theophylline and &bgr;
2
-agonists such as salbutamol, steroids, antiallergic drugs and the like are known.
Further, various tricyclic condensed heterocyclic compounds are proposed.
Examples of such prior arts are mentioned below.
Yakugaku Zasshi,
87,(2), 198-201 (1967) discloses three dihydrodibenz[b,f]oxepin derivatives as the synthetic intermediates of a natural product but no pharmacological action and the like relating to these compounds are described.
U.S. Pat. No. 4,104,280 describes that tricyclc condensed heterocyclic compounds containing an oxygen atom or a sulfur atom as the heterocylic atom and a substituent of —CHRCOOH or —CHRCOOCH
3
(wherein R is a hydrogen atom or a methyl group) on the benzene ring are useful as anti-inflammatory drugs and relaxants.
European Patent Publication No. 0 011 067 A1 suggests that triclyclic condensed heterocyclic compounds containing a sulfur atom as the heterocyclic atom and —(CH
2
)
n
13
A (wherein n is 0 to 4; and A is a heterocyclic residue) as one substituent on the benzene ring are effective for asthma, allergy and the like.
British Patent No. 2,016,466 describes that triclyclic condensed heterocyclic compounds containing an oxygen atom or a sulfur atom as the heterocyclic atom and —CH
2
COR (wherein R is OH, NH
2
, a C
1-5
alkyl group or the like) as one substituent on the benzene ring are useful as anti-inflammatory drugs.
German Patent No. 32 03065 discloses that certain types of triclyclic condensed heterocyclic compounds containing an oxygen atom or a sulfur atom as the heterocyclic atom and various substituents on the benzene ring have pharmacological actions such as analgesia, sedation, antidepression, antispastic action.
European Patent Publication No. 0 003 893 discloses that triclyclic condensed heterocyclic compounds containing oxygen or sulfur as the heterocyclic atom and having —CHR
2
COOR
3
(wherein R
2
is a hydrogen atom or a methyl group; and R
3
is a hydrogen atom or —CH
2
CH
2
OCH
2
CH
2
OH) as one substituent on the benzene ring have pharmacological actions such as anti-inflammation, analgesia and pyretolysis.
German Patent No. 1,302,590 describes tricyclic condensed heterocyclic compounds containing sulfur as the hetero atom and having various substituents on the benzene ring.
U.S. Pat. No. 4,104,280 teaches that 3-hydroxymethyl-benzo[b,f]thiepin containing a sulfur atom as the heterocyclic atom and its derivatives are used in the treatment of allergic diseases such as allergic asthma.
Br. J. Pharmac.,
82, 389-395 (1984) describes 2-hydroxy-methyl-dibenzo[b,f]thiepin-5,5-dioxide which is an antagonist of prostanoids contractile for lung smooth muscles.
Japanese Pharm. Soc. Bull.,
94, 299-307 (1989) suggests that 2-(10,11-dihydro-10-oxodibenzo[b,f]thiepin-2-yl)propionic acid possibly becomes a clinically useful substance as an anti-inflammatory, analgesic and antipyretic drug since it only has a slight effect on circulatory organs and the autonomic nervous system when a considerably large amount is used.
WO Publication 96/10021 describes antioxidative tricylic condensed heterocyclic compounds containing oxygen or sulfur as the heterocyclic atom and having various substitutents on the benzene ring.
WO Publication 96/25927 describes glutamic receptor blockers and cerebral function improving drugs containing oxygen or sulfur as the heterocyclic atom and having various substitutents on the benzene ring.
WO Publication 97/25985 describes tracheal smooth muscle relaxants having compounds containing oxygen or sulfur as the heterocyclic atom and having various substituents on the benzene ring as the effective component.
J. Org. Chem.,
61,5818-5822 (1996) and
Collection Czechoslov. Chem. Commum.,
43, 309 (1978) describe the synthesis of dibenzoxepins and dibenzothiepins.
Terahedron,
40, 4245-4252 (1984) and
Phytochemistry,
31, (3) 1068-1070 (1992) describe dibenzoxepin derivatives derived from a natural substance.
Chem. Pharm. Bull.,
23, (10) 2223-2231 (1975) and
Chem. Pharm. Bull.,
26, (10) 3058-3070 (1978) describe the synthetic methods of dibenzothiepin derivatives and the antiemetic action of these compounds.
J. Chem. Soc. Perkin Trans.
1, 3291-3294 (1991) and
J. Med. Chem.,
26, 1131-1137 (1983) describe the synthetic methods of dibenzoxepin and dibenzothiepin derivatives and the anti-estrogenic action of these compounds.
As stated above, heretofore, various tricyclic condensed heterocyclic compounds have been disclosed, but they cannot be said to be sufficient in respect of therapeutic effect, prolonged action, safety (in terms of preventing side effects) when used as therapeutic drugs for airway disorders such as bronchial asthma, acute or chronic bronchitis, pulmonary emphysema and upper esophagitis and the like and lung diseases, allergic diseases, chronic inflammation and the like. Thus, the development of novel compounds having a broad range of pharmacological actions including an airway smooth muscle relaxing action, an inhibition of airway hypersensitivity and an inhibition of infiltration of inflammatory cells into the airway and, at the same time, high safety (reduced side effects) is demanded.
DISCLOSURE OF THE INVENTION
In view of the above described present situations, the object of the present invention is to provide novel compounds which have a wide range of pharmacological actions such as a clinically useful relaxing action of tracheal smooth muscles, an inhibition of airway hypersensitivity and an inhibition of infiltration of inflammatory cells into the airway.
The present inventors have found as a result of strenuous investigations of tricyclic condensed heterocyclic compounds that certain types of tricyclic condensed heterocyclic compounds having an OH group, or an OH group and an OR group (wherein R is a hydrogen atom or a lower alkyl group) as the substitutent have a wide range of pharmacological actions such as a relaxation of tracheal smooth muscles, an inhibition of airway hypersensitivity and an inhibition of infiltration of inflammatory cells into the airway and, in addition, an excellent prolonged action and safety, and have completed the present invention on the basis of this knowledge. Specifically, the present invention relates to the compounds, their preparation method, uses and intermediates described in the following (1) to (25).
(1) A compound represented by formula (1),
wherein
when the X—Y bond is a single bond, X and Y, which may be the same or different, are each independently any one selected from the group consisting of CW
1
W
2
(wherein W
1
and W
2
, which may be the same or different, are each independently any one of a hydrogen atom, a halogen, a hydroxyl group, a lower alkyl group, a substituted lower alkyl group, a lower alkoxy group, a cycloalkyl group and a cycloalkenyl group), C═O, and C═NOW
3
(wherein W
3
is a hydrogen atom or a lower alkyl group);
when the X—Y bond is a double bond, X and Y, which may be the same or different, are each independently CW
4
(wherein W
4
is any one of a hydrogen atom, a halogen, a hydroxyl group, a lower alkyl group, a substituted lower alkyl group, a lower alkoxy group and an acyloxy group);
Z is any one selected from O, S, S═O and SO
2
;
U is C or N;
R
1
to R
4
, which may be the same or different, are each independently any one selected from the group consisting of a hydrogen atom, a lower alkyl group, a substituted lower

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